Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:10][C:11]2[C:17]([NH:18][NH2:19])=[C:16]([F:20])[CH:15]=[C:14]([Cl:21])[C:12]=2[N:13]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[S:10][C:11]2[C:17]([N:18]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:19])=[C:16]([F:20])[CH:15]=[C:14]([Cl:21])[C:12]=2[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1c(F)cc(Cl)c2nc(Cl)sc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N(N)c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 ml Triethylamine was added to a solution of 4.8 g 2,4-dichloro-6-fluoro-7-hydrazinobenzothiazole in 38 ml toluene. 2.4 ml Pivaloyl chloride was added dropwise and the mixture stirred for 2 hours at room temperature. It was then treated with ethyl acetate and washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography. Yield: 1.36 g=21% of theory
Reaction SMILES: C(S[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[CH:14][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16]2=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:37]([Cl:41])(Cl)(=[O:39])=[O:38]>O>[Cl:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([S:37]([Cl:41])(=[O:39])=[O:38])=[CH:10][CH:11]=2)[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:14]=1
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(SCc4ccccc4)cc3c2=O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cc(Cl)c3ccc(S(=O)(=O)Cl)cc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
A round bottomed flask cooled to 0° C., was charged 7-(benzylthio)-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (0.400 g, 0.948 mmol), DCM (9.03 ml), Acetic Acid (0.226 ml), and Water (0.226 ml). After stirring for 5 minutes at 0° C., sulfuryl chloride (0.077 ml, 0.948 mmol) was added and stirring was continued for an additional 1 hour at 0° C. The reaction was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.342 g of 4-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-7-sulfonyl chloride. m/z (ESI) 399.2 (M+H)+.
Reaction SMILES: F[C:2]1C=C[C:5](C)=[CH:4][CH:3]=1.C[C:10]([CH2:12][CH3:13])=[O:11].[O:14]=O.CCCC>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.C([O-])(=O)C.[Co+2]>[C:10]([OH:11])(=[O:14])[C:12]1[CH:13]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1
Reactant: O=O
Reactant: CCC(C)=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CCCC
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1

Procedure:
Para-Fluorotoluene derivatives B16 are heated at about 90° C. to 110° C. for about 2-3 hours with cobalt diacetate-tetrahydrate and ethyl methyl ketone in acetic acid under pressure of oxygen-butane to produce benzoic acid derivatives B1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].ClCCl.C(OCC)C>C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:15])[C:10](=[S:17])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)C(=O)N(C)Cc1ccc(Cl)nc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)C(=S)N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
In a 250 ml two-necked flask, N-(6-chloro-3-pyridylmethyl)-N-methyl-2-methylpropanamide (6.80 g, 30.0 mmol) is dissolved in 120 ml of benzene, 1.47 g (3.3 mmol) of phosphorus pentasulfide are added and the mixture is heated at reflux for 1.5 hours. After this period of time, the mixture is cooled to room temperature and filtered, and the filtrate is concentrated under reduced pressure using a rotary evaporator. To increase the yield on the same day, the product should be subjected to silica gel column chromatography using the mobile phase dichloromethane/diethyl ether 10/3; Rf=0.8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH2:11][Br:32])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CCl4 (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound G) as a yellow solid. MS: calc'd 445 (MH+), measured 445 (MH+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([C:22](OCC)=[O:23])[C:18](=[O:27])[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=2[F:37])(Br)[CH:16]1[CH3:38].CC(C[AlH]CC(C)C)C.CO>C1COCC1.C(Cl)Cl>[F:11][C:12]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=[O:23])[C:18](=[O:27])[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=2[F:37])=[C:16]1[CH3:38]
Reactant: CCOC(=O)C1=C(C)N(Cc2c(F)cccc2F)C(C)C(Br)(c2cccc(OC)c2F)C1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(C)c(C=O)c2=O)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (3.75 mmol, 3.75 ml of a 1.0M solution in hexanes ) was added dropwise to a stirring solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-3-bromo-5-ethoxycarbonyl-4-pyridone (1.12 g, 2.5 mmol) in THF/DCM (30 mL/ 12 mL), at −78° C. under N2. A suspension was formed at the end of the addition. After 1 hour, an additional aliquot of DIBAL-H (2.5 mmol, 2.5 mL of a 1.0 M solution in hexanes) was added. The reaction was stirred for 1 hour at −78° C. MeOH (50 mL) was carefully added to quench any unreacted DIBAL-H. The solution was concentrated, then partitioned between EtOAc and 1 M HCl. The organic layer was concentrated and purified using flash silica gel chromatography (100% hexanes to EtOAc/hexanes 3/2). The fourth spot which eluted was evaporated to give product as a cream colored solid. 1H NMR (CDCl3, 300 MHz) δ 10.55 (s, 1H), 6.80-7.75 (m, 6H), 5.36 (s, 2H), 3.90 (s, 3H), 2.79 (s, 3H), 2.27 (s, 3H); LCMS=402 (MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2CNC2C=CC=CC=2)O1.Br[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH:48]([CH3:50])[CH3:49])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CO>[NH:38]([CH2:35][C:10]1[CH:11]=[CH:12][C:17]2[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]=1[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH:48]([CH3:50])[CH3:49])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC1(C)OB(c2c(CNc3ccccc3)ccc3ccccc23)OC1(C)C
Reactant: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(-c2c(CNc3ccccc3)ccc3ccccc23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.02 g (5.64 mmol) of N-{[1-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}-aniline, 2.11 g (5.64 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diisopropylaniline, 4.03 g (14.10 mmol) of Na2CO3×10H2O, 63 ml of water, 18 ml of methanol, and 76 ml of toluene was purged with argon for 30 min. To the obtained solution 0.32 g (0.28 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C. Then, it was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 1.56 g (52%) of yellow oil. Anal. calc. for C37H41N3: C, 84.21; H, 7.83; N, 7.96. Found: C, 84.37; H, 7.95; N, 7.84. 1H NMR (CDCl3): δ 7.89 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.88 (m, 1H, 8-H in naphthalene), 7.82 (t, J=7.8 Hz, 1H, 4-H in pyridine), 7.67 (d, J=8.4 Hz, 1H, 3-H in naphtalene), 7.63 (dd, J=7.8 Hz, J=0.8 Hz, 1H, 5-H in pyridine), 7.44-7.49 (m, 2H, 5, 7-H in naphtalene), 7.37-7.41 (m, 1H, 6-H in naphtalene), 7.31 (dd, J=7.8 Hz, J=0.8 Hz, 1H, 3-H in pyridine), 7.11 (m, 2H, 3, 5-H in Ph), 7.02-7.06 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 6.65 (m, 1H, 4-H in Ph), 6.60 (m, 2H, 2.6-H in Ph), 4.17-4.27 (m, 4H, CH2NH and NHCMe2), 3.20 (sep, J=6.8 Hz, 2H, CHMe2), 1.54 (s, 3H, CMeMe′), 1.40 (s, 3H, CMeMe′), 1.02 (t, J=6.8 Hz, 12H, CHMe2).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[CH:15]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1)[C:16]1[S:31][C:19]2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21](=[O:26])[N:22]([CH3:25])[C:23](=[O:24])[C:18]=2[C:17]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>C1COCC1.[Pd]>[CH3:25][N:22]1[C:23](=[O:24])[C:18]2[C:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:16]([CH2:15][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=3)[S:31][C:19]=2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]1=[O:26]
Reactant: CCOC(=O)c1c(C(O)c2ccnc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cc2ccnc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic anhydride (3.33 ml) was added to a solution of the product of step b) (7.34 g) and triethylamine (6.56 ml) in anhydrous THF (150 ml) at room temperature under nitrogen and the mixture stirred for 15 min. 10% palladium on charcoal (500 mg) was added and the mixture hydrogenated at 1 bar for 20 h. It was filtered through Celite, washing with saturated sodium bicarbonate solution (150 ml) then ethyl acetate (300 ml). The organic material was extracted into ethyl acetate (150 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with 1:1 ethyl acetate/i-hexane, to give the sub-title compound as a solid (5.90 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)(CCCCCI)C(OC)=[O:16].[O:26]1CCC[CH2:28][CH:27]1[O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43]CCC(C)(C)C(OC)=O)C(=O)C>>[C:27]([O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:41](=[O:16])[CH:42]=[CH2:43])(=[O:26])[CH3:28]
Reactant: CCCCCC(CCCN(CCCCCC(C)(C)C(=O)OC)C(C)=O)OC1CCCCO1
Reactant: CCOC(=O)CCCCCCBr
Reactant: COC(=O)C(C)(C)CCCCCI
Product: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-bromoheptanoate is replaced by an equimolar amount of methyl 2,2-dimethyl-7-iodoheptanoate. The product of Step A is methyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]-acetamido}-2,2-dimethylheptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)acetamido]-2,2-dimethylheptanoic acid (B).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:44]=[CH:43][C:28]([O:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=4)=[C:27]([Cl:45])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[ClH:45].[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:44]=[CH:43][C:28]([O:29][C:30]4[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=4)=[C:27]([Cl:45])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.1 %

Procedure:
Trifluoroacetic acid (10 mL) was added to tert-butyl 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate (1.26 g), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, 4N hydrochloric acid/ethyl acetate solution was added, and the mixture was concentrated again under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (1.16 g) as a white powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: C#CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C#CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 51.8 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-ynylpiperidin-4-yl)benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-prop-2-ynylpiperidin-4-yl)benzoate (0.257 g, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) in dry toluene (10 mL) with 2M trimethylaluminium (1.250 mL, 2.50 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product crystallised from DCM/diethyl ether to give the title compound (0.245 g, 51.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1cc(F)cc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(F)cc(F)c3)cc2)c1C
Yield: 36.2 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.184 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.09 g, 36%) as a solid. MS calcd. for C26H18F3O2S [(M−H)−] 451, obsd. 451.2.
Reaction SMILES: [C:1]([C:4](=[CH:10]OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C[NH:15][C:16](=[NH:18])[SH:17].S(=O)(=O)(O)O.[C:24]([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:2][C:1]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][N:18]=[C:16]([S:17][CH3:24])[N:15]=1
Reactant: CNC(=N)S
Reactant: CC(=O)[O-]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 175.2 %

Procedure:
To 100 ml of N,N-dimethylformamide, 18.6 g (100 mmol) of ethyl 2-acetyl-3-ethoxyacrylate, 13.9 g (50 mmol) of sulfuric acid methylisothiourea and 8.2 g (100 mmol) of sodium acetate were suspended, followed by stirring at 80° C. for 4 hours. The reaction liquid was cooled and then poured in ice water. The crystal precipitated was filtered, washed with water and dried to obtain 18.6 g (yield: 88%) of ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:38][S:39][CH2:40][CH2:41][C@H:42]([NH2:52])[C:43](=[O:51])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[N:1]1([CH2:6]/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14]([NH:52][C@@H:42]([CH2:41][CH2:40][S:39][CH3:38])[C:43](=[O:51])[CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C\Cn2ccnc2)ccc1CCc1ccc(F)cc1
Reactant: CSCC[C@H](N)C(=O)Cc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1cc(/C=C\Cn2ccnc2)ccc1CCc1ccc(F)cc1)C(=O)Cc1ccccc1

Procedure:
A solution of pentafluorophenyl 5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (0.25 g, 0.5 mmol), (3S)-5-methylsulfanyl-2-oxo-1-phenylpentan-3amine (0.16 g, 0.6 mmol), 1-hydroxy-7-azabenzotriazole (0.075 g, 0.55 mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate and saturated sodium chloride and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound which was isolated as the hydrochloride salt by treatment with HCl/ether. Yield: 70%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH2:12].Cl[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:12]([CH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1

Procedure:
Prepared as in example 5-10 from (2,4-dimethoxyphenyl)methanamine, methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) and benzyl bromide. MS (M−H, 440.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.50 (s, 63H), 3.66 (s, 3H), 4.20 (s, 2H), 4.34 (s, 2H), 6.29 (s, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.12-7.23 (m, 5H), 7.80 (d, J=8.0 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 13.49 (s, 1H).
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O>>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Following the procedure of Example 2 but making noncritical variations 9α-hydroxyandrostenedione (10.00 g.) is reacted with chlorosulfonic acid to give androsta-4,9(11)-diene-3,17-dione, 9.01 g. (90.1% weight yield, 95.7% chemical yield).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C1COCC1>[CH:1]([N:12]([OH:11])[CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:22][CH:23]=1)(=[O:16])=[O:17])=[O:2]
Reactant: O=CO
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)N(O)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To formic acid (0.217 mL) was added acetic anhydride (0.054 mL, 0.576 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. This solution was added to a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.285 g, 0.430 mmol) and formic acid (2 mL) in THF (20 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-s (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from EtOH-ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (0.077 g, 37%).